Developing Novel Strategies to Uncouple Immunotherapy-Induced Autoimmunity from Antitumor Immunity
Abstract
The Fiscal Year 2021 Peer Reviewed Cancer Research Program is mesothelioma. The overarching challenge the project addresses is to improve immunotherapy and eliminate the risks of therapy-associated toxicity. Malignant mesothelioma is an aggressive and incurable cancer caused by asbestos. Immunotherapy is an exciting option for mesothelioma treatment, because it can lead to long-term tumor shrinkage in some patients. However, immunotherapy causes side effects, some of which severely affect vital organs such as the liver, heart, lungs, pancreas, and guts. The immune system is responsible for both tumor shrinkage and side effects. However, we do not understand how immune cells behave in tumors and organs after immunotherapy, and if they attack tumor or organ cells in the same manner. Therefore, there are no strategies to prevent immune cells from causing side effects while preserving the anti-tumor immune response. This project aims to compare attacking immune cells in organs versus tumors after immunotherapy. We propose that understanding differences in immune cells found at the scene of the crime will help us develop new ways to disarm them in organs but not the tumor. As it is unethical to surgically remove organs from cancer patients, we will conduct our study in tumor-bearing animals treated with immunotherapy. We will characterize millions of genes and proteins in individual immune cells from affected organs and tumors and identify drug targets based on their differences. We will subsequently test these drugs in combination with immunotherapy to determine if they can prevent side effects while preserving robust anti-tumor responses. Our project will benefit patients by developing novel strategies to prevent severe immunotherapy-related side effects. In particular, this research will benefit Veterans and their family members who have contracted mesothelioma because of previous exposure to asbestos. Furthermore, countries such as Iraq and Afghanistan are still using asbestos in construction, exposing currently deployed troops to this carcinogen. As immunotherapy is now approved for the treatment of mesothelioma, we expect to see more Veterans and family members with mesothelioma being treated with immunotherapy. Existing studies predict that 30%- 60% of these treated patients develop severe side effects, some of which are life-threatening. Being able to predict and treat immunotherapy-associated toxicities will benefit patients clinically and economically. The long-term benefit of this project is the development of new treatments or drugs to prevent or treat these side effects. Apart from reducing their exposure to asbestos, medical research into improving mesothelioma treatment is the most useful way to benefit Service Members and their family members who have mesothelioma. Dr. Chee’s career goal is to lead an independent research group in the field of mesothelioma immunity, focusing on improving immunotherapy outcomes. A successful Career Development Award reward will support his new line of research at the National Centre of Asbestos Related Disease (NCARD), an Australian Centre of Research Excellence focused on mesothelioma. The environment at NCARD is ideal for Dr. Chee’s development because of mentoring from career guide Professor Anna Nowak and other world leaders in the field of mesothelioma research. There is a world-class research infrastructure and a unique opportunity to study mesothelioma patient samples from a clinical trial. Importantly, there is a path to translation if his research is successful, potentially impacting a planned future clinical trial. The breakthroughs of immunotherapy in clinical oncology, Dr. Chee’s expertise in immunology, and the NCARD research environment will contribute to his development into a leader in the field of mesothelioma immunity.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210403
Entities
People
- Jonathan Chee
Organizations
- United States Army
- University of Western Australia